An estimated 23.6 million people (7 percent of the population) in the United States have diabetes; 90 to 95 percent of all diagnosed cases are type 2 diabetes (CDC, 2007). Obesity and metabolic syndrome are the leading causes of type 2 diabetes. The search for new and more effective therapies to address the growing number of Americans with type 2 diabetes and related conditions is currently hindered by the lack of a research animal model that closely resembles the conditions such as obesity and metabolic syndrome that lead to the human type 2 diabetic condition. Most rodent models currently available commercially that have obesity, metabolic syndrome and type 2 diabetes, have genetic defects in leptin-receptors, leptin or in other hypothalamic peptides. These mono-genetic defects are not common causes for the etiology of obesity and diabetes in the human population. A new mouse model without these defects would more closely resemble the continuum of metabolic disorders that is beginning to be recognized between these human conditions. Thus, a more appropriate model for obesity, metabolic syndrome, type 2 diabetes and the consequent complications is needed for this work. In 2004, PreClinOmics (PCO) began a promising program to develop a new mouse model without leptin/leptin- receptor and other genetic defects which would affect hypothalamic function, by crossing two inbred mouse models with the propensity to develop diet induced obesity with insulin resistance. The long-term goal of this project is to create a mouse model that will be accepted by the biotech or pharmaceutical industries, and the research community to advance the study of and the development of therapies for obesity, metabolic syndrome and type 2 diabetes in humans. Phase II of the project will focus on the continued development, defining, and characterization of this new obese mouse model. The project has four specific aims: 1) Continue development of the Fatzo mouse to achieve genetic and phenotypic homogeneity of traits for obesity and metabolic syndrome. Confirm normal function of LepR and Lep genes by experimental evidence of responsiveness to exogenous leptin. 2) Identify and confirm the presence of known components of human metabolic syndrome/type 2 diabetes in the Fatzo mouse. Components to be examined include reduced energy expenditure, dyslipidemia, hypertension, dysfunctional glucocorticoid regulation, low grade inflammation, beta cell dysfunction and activated renin-angiotensin-aldosterone-system (RAAS). 3) Confirm the models' responsiveness in prevention and treatment strategies to agents marketed for the clinical treatment of metabolic syndrome/type 2 diabetes. 4) Confirm the model's responsiveness to dietary manipulation to maintain the pre-diabetic state as well as to accelerate the progression to frank diabetes. PUBLIC HEALTH RELEVANCE: Research to identify new treatments for human obesity and its related conditions is hindered by the lack of relevant animal models. This effort will describe a new mouse model that reflects the human disease and is therefore applicable for the evaluation of potential treatments.